We have located a genetic element at 1p31 linked to measures of insulin secretion and nutrient partioning. We have genotyped additional markers in the regions of linkage on chromosome 1, and have completed a YAC contig and physical map this region covering approximately 9 cM to further refine and localize this genetic element that influences this aspect of insulin secretion. The map spans approximately 9 megabases of DNA includes loci encoding phosphoglucomutase 1 (PGM1), janus kinase 1 (JAK1), phosphodiesterase 4B (PDE4B), c-JUN (JUN), GADD45 (GADD45) and the leptin receptor (LEPR). The structure of the leptin receptor, a candidate gene, was deduced and all 20 exons sequenced in 20 individuals. Sequence analysis uncovered several nucleotide substitutions that result in amino acid substitutions. Two common polymorphisms in LEPR were genotyped in 1300 Pima Indians. The amino acid substitutions at amino acid 223 are associated with changes in circulating leptin levels and with NIDDM. Studies of the effect of this polymorphism on the function of the leptin receptor are just being completed. This project has been terminated.